Enhancing venetoclax activity in hematological malignancies.

INTRODUCTION: Targeting anti-apoptotic pathways involving the BCL2 family proteins represents a novel treatment strategy in hematologic malignancies. Venetoclax, a selective BCL2 inhibitor, represents the first approved agent of this class, and is currently used in CLL and AML. However, monotherapy is rarely sufficient for sustained responses due to the development of drug resistance and loss of dependence upon the targeted protein. Numerous pre-clinical studies have shown that combining venetoclax with other agents may represent a more effective therapeutic strategy by circumventing resistance mechanisms. In this review, we summarize pre-clinical data providing a foundation for rational combination strategies involving venetoclax. AREAS COVERED: Novel combination strategies in hematologic malignancies involving venetoclax, primarily at the pre-clinical level, will be reviewed. We emphasize novel agents that interrupt complementary or compensatory pro-survival pathways, and particularly mechanistic insights underlying synergism. PubMed, Cochrane, EMBASE, and Google scholar were searched from 2000. EXPERT OPINION: Although venetoclax has proven to be an effective therapeutic in hematologic malignancies, monotherapy may be insufficient for maximal effectiveness due to the development of resistance and/or loss of BCL2 addiction. Further pre-clinical and clinical development of combination therapies may be necessary for optimal outcomes in patients with diverse blood cancers.